Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands

J Med Chem. 2021 Aug 26;64(16):12132-12151. doi: 10.1021/acs.jmedchem.1c00770. Epub 2021 Aug 17.


Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure-activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo. Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / pharmacology
  • Coordination Complexes / therapeutic use*
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Immunologic Factors / chemical synthesis
  • Immunologic Factors / pharmacology
  • Immunologic Factors / therapeutic use*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Male
  • Maleimides / chemical synthesis
  • Maleimides / pharmacology
  • Maleimides / therapeutic use*
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Platinum / chemistry
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology
  • Prodrugs / therapeutic use*
  • Structure-Activity Relationship
  • Succinimides / chemical synthesis
  • Succinimides / pharmacology
  • Succinimides / therapeutic use


  • Antineoplastic Agents
  • Coordination Complexes
  • Immunologic Factors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Maleimides
  • Prodrugs
  • Succinimides
  • Platinum